This proposal describes the development of a Genetics Research Center (GRC) at the University of Chicago to be part of a cooperative Inflammatory Bowel Disease (IBD) Genetics Consortium. The GRC will serve the dual functions of a) proposing and performing approved studies which will make optimal use of Consortium resources and strengths, (Specific Aims I and II), and, b) recruiting appropriate patients as defined by the Consortium Steering Committee, as well as appropriately phenotyping patients using criteria commonly agreed to by the Consortium (Specific Aim III). We have recently established that three polymorphisms within Nod2 are highly associated with susceptibility to familial Crohn's disease (CD). While the signaling partners and ligands of Nod2 are incompletely defined at present, it is known that RICK/RIP2/CARDIAK, a serine-threonine kinase which binds Nod2, is recruited to the TNFR1 complex, as well as to other members of the TNFR superfamily such as Fas and CD40. Because Nod2 polymorphisms are neither necessary nor sufficient for CD expression, we hypothesize that additional genes increasing susceptibility to CD can be identified either through stratifying linkage analyses based on Nod2 genotypes (specific aim I) or through consideration of candidate genes involved in signaling pathways involving Nod2 (specific aim II).
Specific Aim I : To identify the CD susceptibility gene on chromosome 16p which positively interacts with Nod2 to increase disease risk. Redefining as """"""""affected"""""""" only the subset of CD individuals carrying the major Nod2 risk alleles, we demonstrate evidence for linkage in the chromosome 16p region independent of the contribution from Nod2 on chromosome 16q12. The identification of genes positively interacting with Nod2 will provide critical insight into disease pathogenesis.
Specific Aim II. To utilize information from a stratified Consortium linkage analysis to prioritize and test genes in the signaling pathway involving Nod2 for association to CD. Increased priority is given to those genes involved in both Nod2 and TNF signaling pathways, such as RICK/RIP2/CARDIAK. III. To develop a Clinical Core which will be responsible for additional patient recruitment and phenotyping as mandated by the Consortium Steering and Planning Committee. To collect additional African-American patients with CD. Preliminary data demonstrate that comparative studies in African-Americans will provide important insight into disease pathogenesis.
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